Workup for Persistently Low Alkaline Phosphatase
The primary concern with persistently low ALP is hypophosphatasia (HPP), a genetic disorder that can be misdiagnosed as osteoporosis and inappropriately treated with bisphosphonates, which may worsen outcomes. 1, 2
Initial Laboratory Evaluation
Measure the following tests to confirm low ALP and assess for HPP:
- Repeat total ALP to confirm persistent elevation (low on ≥2 occasions separated by at least 2 months) 2, 3
- Vitamin B6 (pyridoxal-5-phosphate) - elevated levels strongly suggest HPP as this is a substrate that accumulates when tissue-non-specific alkaline phosphatase is deficient 1, 4, 5, 3
- Serum calcium and phosphate - look for hypercalcemia and hyperphosphatemia, which can occur in HPP due to impaired bone mineralization 1
- Parathyroid hormone (PTH) and 25-hydroxyvitamin D - to exclude secondary causes of low bone turnover and other metabolic bone disorders 1
- Bone-specific ALP - may be low even when total ALP is normal, making it a more sensitive marker for HPP 4
Critical Clinical History Elements
Obtain specific details about:
- Dental history - premature loss of deciduous teeth (before age 5), dental abscesses without caries, periodontal disease, or "gray gums" in childhood are highly suggestive of HPP 1, 5
- Fracture history - recurrent stress fractures, atypical femoral fractures, or fractures with minimal trauma 1, 6, 2, 5
- Musculoskeletal symptoms - chronic widespread pain (may mimic fibromyalgia), joint pain, muscle weakness, or enthesopathies 1, 6
- Medication review - bisphosphonates, denosumab, or other antiresorptive agents can lower ALP and may cause atypical fractures in undiagnosed HPP patients 1, 6, 2
- Nutritional assessment - malnutrition, zinc deficiency, magnesium deficiency, or vitamin C deficiency can cause low ALP 3
Physical Examination Findings
Assess for:
- Lower limb alignment abnormalities (bowing) 1
- Spine deformities (lordosis, kyphosis, scoliosis) 1
- Joint examination for enthesopathies, chondrocalcinosis, or calcific periarthritis 1, 3
- Growth parameters if pediatric patient 1
Genetic Testing
If vitamin B6 is elevated or clinical suspicion is high, proceed with ALPL gene sequencing to identify pathogenic variants that confirm HPP 1, 4, 5, 3. Note that some patients may have normal ALPL sequencing but still have HPP due to mutations in regulatory regions or epigenetic changes 3.
Additional Metabolic Workup
Consider measuring:
- Urinary phosphoethanolamine (PEA) - elevated in HPP as another substrate that accumulates 1, 3
- Zinc and magnesium levels - deficiencies can cause acquired low ALP 6, 3
Imaging Considerations
If HPP is suspected or confirmed:
- Obtain dental radiographs for comprehensive dental evaluation 1
- Consider skeletal radiographs if bone pain or deformities are present - look for osteomalacia, pseudofractures, or stress fractures 1
- Bone densitometry (DXA) may show osteopenia/osteoporosis, but this represents defective mineralization rather than true osteoporosis 2, 5
Critical Management Pitfall
Do NOT initiate bisphosphonates or denosumab in patients with low ALP until HPP is excluded - these antiresorptive agents are relatively contraindicated in HPP and may precipitate atypical femoral fractures 1, 2, 5. If a patient is already on these medications, consider discontinuation pending workup 2.
Differential Diagnosis to Exclude
Beyond HPP, consider:
- Nutritional deficiencies - zinc, magnesium, vitamin C, or severe malnutrition 3
- Endocrine disorders - hypothyroidism, vitamin D deficiency (though PTH should be elevated) 3
- Severe acute illness - low ALP can be an epiphenomenon of critical illness 3
- Medications - clofibrate, glucocorticoids (chronic use) 3
Prevalence Context
Low ALP occurs in approximately 9% of osteoporosis clinic patients, with 3% of those having confirmed HPP 2. Among patients with persistently low ALP (≥2 measurements), the prevalence of HPP rises significantly 2. This condition is substantially underdiagnosed, particularly in patients presenting with chronic pain syndromes like fibromyalgia 6.